We propose to continue our investigations on the role of adhesion receptors in promoting leukocyte function in homeostasis and in pathological conditions. Our proposal is mainly concerned with the platelet and endothelial selectins, mediating leukocyte rolling, and the intercellular adhesion molecule-1 (ICAM-1) that promotes leukocyte firm adhesion and is not restricted to the vasculature. We will focus on the biological processes of inflammation, atherosclerosis and obesity, all of which are of primary clinical importance. The first specific aim involves the biological roles of the selectins. We found that during injury or in inflammation P-selectin is proteolytically shed into blood. We will now investigate the mechanisms involved in P-selectin shedding and the function of the soluble P-selectin fragment in inflammation and thrombosis. For this, we will engineer a transgenic mouse overexpressing soluble P-selectin. We intend to continue our studies on the role of the selectins in the development of atherosclerotic lesions using selectin-deficient mice on either LDL-receptor or ApoE-deficient backgrounds and evaluate the potential of inhibitors of the selectins and their ligands as therapeutic agents. In the second aim, we will engineer systemic and conditional mutants in the ICAM-1 gene in mice and investigate the role of ICAM-1 in atherosclerosis. Our third aim focuses on the role of leukocyte adhesion receptors in preventing obesity. We have recently discovered that mice deficient in ICAM-1 or the leukocyte integrin Mac-1 become obese in old age or when fed a high fat diet. We want to understand the molecular and cellular mechanisms involved in the novel concept that leukocytes regulate body weight. We will take three approaches: Cell culture studies using wild-type and adhesion molecule-deficient leukocytes and adipocytes; animal studies investigating thermogenesis and fat metabolism of the ICAM-1-deficient mouse; and human studies that will evaluate the possibility that human mutations in the ICAM-1 gene lead to obesity. Our efforts should enhance understanding of the molecular mechanisms involved in processes leading to chronic inflammation, atherosclerosis and obesity. We will begin to test the potential therapeutic values of anti-adhesion therapy using inhibitors of endothelial and leukocyte adhesion receptors in mouse disease models.